The TGF-betas are important growth regulators with diverse tissue and cell- specific effects. Three isoforms, TGF-beta1, TGF-(beta2, and TGF-beta3, show distinct expression patterns during mouse embryogenesis. Although the TGF-betas bind cell surface receptors with some affinity differences, their effects are qualitatively identical when appropriate receptor subtypes are expressed. Mice lacking TGF-beta1 die from inflammation within weeks of birth, when TGF-beta1 from maternal transfer becomes deplete. Genetic loss of TGF-beta2 engenders perinatal death with developmental defects in multiple tissues. In contrast, elimination of TGF-beta3 causes more focused pathology and death within 24 hours. These mice exhibit cleft palate and failure to suckle, and airway and pulmonary defects. TGF-beta1 and TGF-beta2 levels are normal in TGF-beta3 knockout mice, allowing a common interpretation that TGF-beta3 has a specific function that other isoforms cannot support. Rather, we propose that temporal and spatial expression of TGF-beta3, and not TGF-beta3 per se, predominate in this situation. To address this, we propose to substitute the TGF-beta1 coding sequence downstream of the regulatory region of the TGFbeta3 gene. We hypothesize that expression of TGF-beta1 under control of the native TGF- beta3 gene promoter will rescue the TGF-beta3 mutant phenotype, whereas a similar substitution with targeting cassette will mimic TGF-beta3 knockouts.